Macrophages Are Phenotypically and Functionally Diverse across Tissues in Simian Immunodeficiency Virus-Infected and Uninfected Asian Macaques

Abstract

Macrophages regulate tissue immunity, orchestrating the initiation and resolution of antimicrobial immune responses and repair of damaged tissue architecture. Their dysfunction can, thus, manifest in either pro-and anti-inflammatory responses. Indeed, despite the importance of macrophage function in health and disease, the role of tissue-resident macrophages in human immunodeficiency virus (HIV) disease progression remains incompletely defined. Here, we use flow cytometry to assess the phenotypes and functions of macrophages isolated from the spleens, axillary lymph nodes, colons, jejuna, and livers of healthy and chronically simian immunodeficiency virus (SIV)-infected Asian macaques, the prominent nonhuman primate model for HIV infection. Our data demonstrate that macrophages from healthy animals exhibit considerable phenotypic and functional heterogeneity across tissues and across a variety of stimuli. Further, our analysis reveals changes in the lipopolysaccharide (LPS) responsiveness of macrophages isolated from SIV-infected animals. We anticipate that our findings will inform future research into macrophage-directed immunity across a variety of primate diseases. IMPORTANCE These findings highlight the functional and phenotypic heterogeneity of tissue macrophages in different anatomic sites and as a result of SIV infection. We believe that our data will lead to novel therapeutic interventions aimed at altering the proinflammatory capacity of tissue macrophages in progressively HIV-infected individuals.N onhuman primates (NHPs) serve as an ultimate model for studying some human diseases and development. NHPs share upwards of 90% genetic similarity to humans, exhibit a largely parallel developmental program, and mirror human anatomy and anatomic process (1). The zoonotic transmission of pathogens from NHPs to humans remains a significant concern and has been documented to include herpes simian B virus, Marburg virus, and simian immunodeficiency virus (SIV), the ancestral progenitor of human immunodeficiency virus (HIV). Despite the many evolutionarily conserved similarities between human and divergent NHP species, differences in disease outcome are apparent. Importantly, HIV type 1 (HIV-1) infection in humans and SIV infection in Asian macaques result in similar, severe disease progressions, while SIV infection in NHPs of African origin results in a nonpathogenic course of disease (2). Given the limited divergence exhibited between primate species, a complete dissection of immunological processes in NHP species will yield critical information regarding potential mechanisms of disease progression and remission in human patients.SIV infection in Asian macaques and HIV infection of humans are characterized by persistent immune activation that is attributable, in part, to damage to the gastrointestinal barrier and subsequent microbial translocation (3, 4). The gastrointestinal lumen is estimated to contain 10 14 commensal and potentially pathogenic microbes that are kept separate from the underlying tissu...

Macrophages and Myeloid Dendritic Cells Lose T Cell–Stimulating Function in Simian Immunodeficiency Virus Infection Associated with Diminished IL-12 and IFN-α Production

“…Macrophages accumulate in lymph nodes and gut mucosa in both SIV and HIV infection (15, 23, 32, 33), and the level of monocyte turnover is predictive of disease progression (21, 22). Our data suggest that loss of macrophage function in stimulating adaptive T cell responses may be a critical component in progressive HIV and SIV infection.…”

“…Lymph node macrophages lost capacity to produce IFN-α, consistent with previous studies (15), although macrophages in gut mucosa of untreated HIV-infected patients produce proinflammatory molecules, suggesting there may be anatomical differences in macrophage function (32). Indeed macrophages in humans and rhesus macaques have considerable heterogeneity across tissues (33, 34), and it will be important in future studies to determine if T cell-stimulating function of the different macrophage subsets is uniformly or differentially affected by SIV infection and how this relates to disease progression.…”

Persistent accumulation of gut macrophages with impaired phagocytic function correlates with SIV disease progression in macaques

“…These findings have implications for macrophage recruitment and accumulation as a central mechanism in the pathogenesis of inflammatory bowel disorders . Macrophages also infiltrate the intestine in HIV‐infected humans and SIV‐infected macaques . However, whether macrophage accumulation in intestine reflects a beneficial or detrimental role in HIV/SIV pathogenesis remains unknown.…”

Continuous Antigenic Stimulation of DO11.10 TCR Transgenic Mice in the Presence or Absence of IL-1β: Possible Implications for Mechanisms of T Cell Depletion in HIV Disease

“…In this scenario, both the cytopathic effects of HIV on CD4 + T cells and the deleterious impact of HIV infection on CD4 + myeloid cells (including antigen-presenting cells) capable of IL-1β production (38) might cumulatively lead to altered homeostasis of the T cell lineage, with less cell division over time. Although further work is clearly required to extend these findings to humans (e.g., in studies examining IL-1β blockade in the context of treated HIV disease) (39), our data suggest that interventions designed to restore innate immunity in general (or the production of IL-1β in particular) might help to reinstate complete T cell immunity in patients treated with ART.…”